The proposed research concerns the chemical synthesis of new vitamin D3 (cholecalciferol) analogs and metabolites for studies of their solution structure, for biological and possible clinical assay, and in certain cases for studies of their further chemical transformations. A new synthetic approach to vitamin D will also be investigated; it involves as a key step the thermal sigmatropic rearrangement of vinyl allenes. The hypothesis has been put forward that the presence of a 1 alpha-hydroxyl (or pseudo-1alpha-hydroxyl) substituent in vitamin D-like 9,10-seco-steroids possessing a topology similar to that of 1alpha,25-dihydroxy-vitamin D3 is a key condition for biological activity. Based on structure-activity correlations which included the conformational analyses of these steroids, we proposed recently that this key hydroxyl must occupy the equatorial as opposed to the axial orientation for optimization of biological activity. As a test of this hypothesis and for establishing other structural and stereochemical conditions necessary for optimum hormonal activity, studies of analogs such as the following are planned: 3alpha-methyl-, 3beta-methyl- & 3,3-dimethyl 3-deoxy-1alpha-hydroxyvitamin D; 10,19-dihydrovitamin D (dihydrotachysterol); A-nor-, 19-nor-, A-homo- and side chain nor- and homo-vitamin D; and several additional analogs with 25-OH groups and stereoisomeric (double bonds and hydroxyls) functional groups. We also plan to look for additional examples of analogs with anti-vitamin D activity recently uncovered in this laboratory for the first time. The analogs and the synthetic intermediates leading to them will be fully characterized both chemically and spectroscopically. Each new analog synthesized will be submitted for biological assay. The availability of new analogs will allow a more detailed investigation at the molecular level of the mechanism of action of vitamin D.